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All 23 posts Subject: Cyclohexenylacetonitrile for Morphinans Please login to post Down

Pimpo
(Newbee)
10-06-03 15:45
No 462981
      Cyclohexenylacetonitrile for Morphinans
(Rated as: good read)

Cyclohexylidenecyanoacetic Acid and-Cyclohexenylacetonitrile
Organic Syntheses, Coll. Vol. 4, p. 234 (http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0234)

I guess that 1-cyclohexenylacetonitril might easily be converted (LiAlH4?) to 2-(1-cyclohexenyl)-ethylamine, which is in turn useful for making racemorphan/levorphanol (cf. Post 319328 (blondie: "TITLE Preparation of useful intermediates of ...", Chemistry Discourse)). I saw an Indian company offering both the amine and nitrile on the web today and I figured that they make the amine from the nitrile, I never heard of any other way of making it anyway.

Rhodium
(Chief Bee)
10-06-03 19:23
No 463018
User Picture       How to link articles from http://www.orgsyn.org
(Rated as: good read)

Linking to individual preparations at the Organic Syntheses website is easy as soon as you understand their URL logic, see here:

Org. Syn. Coll. Vol. 4, p. 234: 1-Cyclohexenylacetonitrile (http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0234)

Note the last part of the URL: prep=cv4p0234 - corresponds to - Coll. Vol. 4, p. 234

Pimpo
(Newbee)
10-07-03 15:21
No 463208
      article on morphinane-synthesis
(Rated as: excellent)

Thanks alot for your information Rhodium, I will make use of it in the future. Finally having found a synthesis for cyclohexenylacetonitrile greatly increased my interested in the morphinane series, so I decided to go through the literatue today (even though I'm so f**king tired that I hurt myself badly this morning, toenail turned blue and hurts alot frown ). Well anyway, I was quite succesful smile , here it is:

translated excerpts taken from Helvetica Chimica Acta, 23 (1950), p. 1437-1448, O. Schnider and J. Hellerbach - "187. Synthese von Morphinanen (2. Mitteilung)"

(p. 1443-1444)

A. Synthesis of Cyclohexene-1-yl-ethylamine

[..]

cyclohexene-(1)-yl-ethylamine

1. from cyclohexene-(1)-yl acetamide

To a well stirred suspension, cooled to 0 °C, of 139 g cyclohexene-(1)-yl acetamide (1 mol) in 6000 ml absolute ether is added dropwise under nitrogen in portions within ca. 15 min 76 g (2 mol) well powdered LiAlH4. The reaction product [not rather mixture?] is stirred over night and then heated for 15 min. After destroying the excess LiAlH4 with water [dangerous?] the ethereal solution is decanted and the residue washed with ether. After drying the ethereal solution with anhydrous K2CO3 the ether is distilled off and residual cyclohexenyl-ethylamin distilled under water pump pressure. Bp. 75-76 °C (10 mm). Yield 82.5 g (66% of theory).
The hydrochloride melts with decomposition at 160-163 °C
[elemental analysis info omitted]

2. from cyclohexene-(1)-yl-acetonitrile

a) with LiAlH4: To a solution of 42 g LiAlH4 (1.1 mol) in 2000 ml absolute ether is added under nitrogen atmosphere at 0 °C 121 g cyclohexene-(1)-yl-acetonitrile in 800 ml absolute ether with good stirring and stirring is continued for 2 h. After destroying the excess LiAlH4 with water and adding conc. NaOH until the ethereal solution is completely clear the reaction product is worked up as in the example before. Yield 89.5 g (66% of theory).

b) with catalyst: 1 kg cyclohexenyl acetonitrile is dissolved in 2000 ml methanol and reduced in the presence of 250 g Raney cobalt [anybody know about that?] in an autoclave at 60 °C under a pressure of 95 atm of hydrogen. After the uptake of 2 mol hydrogen the reduction is stopped and the catalyst filtered off. The residue that remains after distilling off the methanol is fractionated over a column; after a small forerun the cyclohexenyl ethylamine distills at 75-76 °C (10 atm). Yield ca. 90%.

... will be continued soon, too busy, too tired right now.

Rhodium
(Chief Bee)
10-07-03 20:44
No 463253
User Picture       Very Interesting!

Very Interesting! Please go on, and definitely continue up to the point where they prepare an active compound from this.

Pimpo
(Newbee)
10-08-03 13:29
No 463362
      ...more on morphinanes
(Rated as: excellent)

Thanks for your attention, Rhodium. The rest of the synth basically follows DopaMan's outline https://www.rhodium.ws/chemistry/levorphanol.html, but of course there are a lot more details given:

... continuing from p. 1444 - p. 1446, all elemental analysis info omitted

Synthesis of N-Methyl-morphinane

phenylacetic acid-(cyclohexenyl-ethyl)-amide

To 125g Cyclohexenyl-ethyl amine (1 mol) in 250 ml absolute benzene is slowly added with cooling in ice and stirring 85 g (0,55 mol) phenylacetyl chloride in 170 ml absolute benzene. The reaction product [?] is allowed to stand for 30 min at RT and is then warmed for another 30 min on a water bath. After filtering off the Cyclohexenyl-ethyl amine hydrochloride the benzene solution is washed with sodium bicarbonate and the benzene is distilled off; the residue (123 g), which solidifies, consists of phenylacetic acid-(cyclohexenyl-ethyl)-amide. Mp 69 - 71 °C from benzene-petrolether. For analysis the product is distilled at high vacuum[is that the right word blush ? I mean like really low pressure.].

1-benzyl-2-methyl-1,2,3,4,5,6,7,8-octahydro-isochinoline

243 g (1 mol) phenylacetic acid-(cyclohexenyl-ethyl)-amide are heated with 730 g P2O5 in 1200 ml benzene for 45 min and then allowed to stand for 2 h at RT. To the reaction product[?] is added ice with strong cooling and the aqueous phase is separated from the benzene, which contains small amounts of the starting material. The base is precipitated from the aqueous phase by addition of solid KOH at 0 °C and extracted with ether and dried. After distilling off the ether there remain 178g of a light yellow oil, to which, dissolved in 80 ml aceton, there is added a solution of 200 g methyl bromide [yuck! the iodide might do too?] in 300 ml anhydrous acetone, and this is allowed to stand for 12 h.

The residue, which remains after removing the acetone in vacuo, is dissolved in little water and extracted with ether. The aqueous solution of the quaternary salt, after addition of 56 g KOH in methanol, is reduced in the presence of Raney-Nickel in an autoclave at 50 atm H2. The reduction product is dissolved is dissolved in benzene, after filtering off the catalyst and removing most of the methanol in vacuo, and then washed with water. After the usual workup the 1-benzyl-2-methyl-1,2,3,4,5,6,7,8-octahydro-isochinoline distills at 106 - 108 °C (0.01 mm). There is obtained 85.8 g of a yellow oil, the hydrochloride of this melts at 195 °C and does not depress the mp in a mixture with benzyl-methyl-octahydro-isochinoline HCl obtained by another method [1,2].

N-methyl-morphinane

The cyclization of the benzyl-N-methyl-octahydro-isochinoline to N-methyl-morphinane is done as known [1] and yields a base of bp 110 °C (0.04 mm), phosphate mp 141 - 145 °C.

C. Synthesis of 3-Hydroxy-N-alkyl-morphinanes [this is racemorphan]

p-methoxy-phenylacetic acid-(cyclohexenyl-ethyl)-amide

a) To 125 g (1 mol) cyclohexenyl-ethylamine in 300 ml benzene is added dropwise at 0 °C with good stirring within 30 min a solution of 92.3 g (0,5 mol) thionyl chloride in 92 ml benzene. The reaction starts imidiatelly and is finished after 2 h standing at RT. After workup as described for phenylacetic acid-(cyclohexenyl-ethyl)-amide the p-methoxy-phenylacetic acid-(cyclohexenyl-ethyl)-amide melts at 81 - 82 °C, after crystallization from petrolether. There are obtained 123 g, i.e. 90 % of theory.

b) the same product is obtained in virtually theoretical yield when equimolar [better yield and no waste of precious amine!] amounts of cyclohexenyl amine and p-methoxy-phenylacetic acid are refluxed in xylene, until the calculated amount of water has been removed with a trap [you know what I mean].

1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinoline

273 g (1 mol) p-methoxy-phenylacetic acid-(cyclohexenyl-ethyl)-amide is refluxed in 1000 ml benzene with 307 g POCl3 for 3 h. After cooling the reaction product [?] is poured on ice and the aqueous phase is made alkaline with ca. 30 % NaOH. The precipitated base is extracted with ether and the ethereal solution washed with water and dried. The crude 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinoline, which remains after distilling off the ether, is dissolved in the five-fold amount of methanol
and reduced at normal pressure in the presence of 50 g Raney-Nickel.

After the calculated amount of hydrogen has been taken up, the catalyst is filtered off, and the alcoholic solution made slightly acidic with 48 % HBr. Then the methanol is removed in vacuo and the residue recrystalized from water. There are obtained 170 g (50 % of theory) 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinoline hydrobromide, mp 198 - 199 °C.

1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydro-isochinoline

From a solution of 338 g (1 mol) methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinoline in water the free base is precipitated with conc. NaOH and dissolved in 600 ml MeOH. To the solution is added 90 ml of ca. 40 % formaline and this is allowed to stand for 2 h at RT and then reduced after adding 100 g Raney-Nickel. The reduction stops after the calculated amount of hydrogen is taken up. After filtering off the catalyst methanol and water are removed with addition of benzene in vacuo and the residual oil is distilled at high vacuum. The 1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydro-isochinoline distills at 117 - 119 °C (0.008 mm). The distillate is dissolved in acetone and the calculated amount of oxalic acid is added. There are obtained 235 g of oxalate, which is recrystalized from water or alcohol, mp 163 - 164 °C. Yield 65 % of theory. Hydrochloride mp 149 - 151 °C. The mixed mp with the hydrochloride from Schnider & Grüssner was not depressed.

3-oxy-N-methyl-morphinane

The oxalate is converted to 3-oxy-N-methyl-morphinane with 100 % H3PO4 as described in [1] by Schnider & Grüssner, giving the yield stated there, mp 251 - 253 °C; hydrobromide mp. 192 - 194 °C; tartrate mp 147 °C. From the mother liquor there can be obtained in minute amounts a compound of the same ["bruttoformel" = same percentage of elements, I think this might be the corresponding isomorphinane reported in other literature]. The base melts at 202 - 203 °C, hydrobromide mp 282 - 283 °C.

[The rest is about dioxy-morphinans and ethers of morphinans, this is omitted, as far as I know these are not or not very active.]

refs:

[1] 1. Mitt. O. Schnider & A. Grüssner, Helv. Chim. Acta 32, 821 (1949).
[2] R. Grewe and co-workers, Naturwiss. 33, 333 (1946) [couldn't get this, anybee want to try?]; Z. angew.Chemie, 59, 194 (1947) [I got this one too, interesting read, but NO experimentals]; A. [?] 564, 161 (1949).

Great article, unfortunately some steps (e.g. autoclave) seem to bee somewhat a problem for all but the best-equipped bees. Well let's see what comes from this. I'll post something on morphinane SARs soon. I can tell you that much, there are some that let levorphanol look like light-beer compared to whiskey cool , at least in animals. Not harder to make, most likely too.

Pimpo
(Newbee)
10-10-03 12:20
No 463773
      morphinane SARs
(Rated as: excellent)

This is from

MEDICINAL CHEMISTRY
A Series of Monographs
Volume 5: George DeStevens (Ed.). Analgetics. 1965
ACADEMIC PRESS New York and London
pages 142-143

A book that I cited before (cf. Post 456856 (Pimpo: "2-aminoindane as analgetic", General Discourse)). It is definately on of the best concerning analgesics, which have read!

TABLE III

ANALGETIC ACTIVITY OF N-METHYLMORPHINANS WITH SUBSTITUENTS IN THE AROMATIC PORTION

   Mouse, subcutaneous (mg/kg)
   ---------------------------
R Salt    ED 50    LD 50
----------------------------------------------------
H(a)    H3PO4 11.3 92
3-OH(b) tartrate    0.5    365
3-OCOCH3(b) tartrate    2.2    -
3-OCH3(b) HBr 3.0    260
3-OH, 2-CH3(b) HCl inactive 200
Morphine    HCl 2.1    576
Codeine HCl 14.0 270

TABLE IV

ANALGETIC ACTIVITY OF (-)-3-HYDROXY-N-SUBSTITUTED MORPHINANS

   Mouse, subcutaneous (mg/kg)
   ---------------------------
N-Substituent Salt ED 50 LD 50
--------------------------------------------------------
H HBr    60.2    222
CH3 tartrate 0.5 365
CH2CH3    HBr    9.5 243
CH2CH2CH3 HBr    inactive   530
CH2(CH2)2CH3    tartrate 1.1 -
CH2(CH2)3CH3    HCl    0.4 158
CH2(CH2)4CH3    HCl    0.5 -
CH2Ph HBr    inactive   -
CH2CH2Ph    HBr    0.14    -
CH2COPh HCl    0.10    > 400
CH2CH(OH)Ph HCl    0.09    225
CH2(CH2)2Ph HBr    25.4    > 400
CH2(CH2)3Ph tartrate 3.6 > 400
CH2CH2-cyclo-C6H11    HCl    2.6 > 750
CH2CH2-4-pyridyl    tartrate 0.09    500
CH2CH2-4-piperidino H2SO4    inactive   -
CH2CH2-N-morpholino salicylate 70.1    > 600
CH2CH2-2-furyl    HCl    0.01    250
CH2CH2-2-thienyl    HCl    0.02    502
CH2CH2-Ph-p-NH2 base 0.02    111
CH2CH2-Ph-m-NH2 HCl    0.04    176
CH2CH2-Ph-o-NH2 base 0.7 665
CH2CH2-Ph-p-OH    HCl    0.2 675
CH2CH2-Ph-p-OCH3    tartrate 0.2 > 400
CH2CH2-Ph-p-NO2 HCl    0.04    > 600
CH2CH2-3,4-methylene- HCl    0.07    > 800
dioxyphenyl
CH2CH2-Ph-p-SCH3    base 0.05    > 600

My conclusion: The 3-hydroxy substituent on the aromatic ring seems to be by far the most active substituent on this portion of the molecule. We can clearly see, that there are a lot of possibilities to make more effective yet less toxic derivatives by changing the N-substituent. I think the synthesis wouldn't be much harder in some intersting cases.

Pimpo
(Newbee)
10-10-03 12:24
No 463774
      technical problems (again)

These don't seem to end. The tables looked fine in the preview. I can't edit the post, because the text window is empty and instead the text is displayed outside of the text window, where it can't be edited. I guess, I once again need your help here, Rhodium! Thanks.

josef_k
(Hive Bee)
10-10-03 13:01
No 463776
      Wow, this is interesting numbers.

Wow, this is interesting numbers. That book seems like it might be worth looking up.
I wonder why the O-acetyl version of racemorphan is less potent?

Pimpo
(Newbee)
10-11-03 15:38
No 464001
      thoughts about morphinanes

josef_k, the book is of course out of date, but on the opiod families known at the time it is really quite extensive and a great source of references.
Concerning the activity of levorphanol compared to its acetyl derivative: I am too rather surprised by this, but one factor that might be important here is that levorphanol is less subject to metabolization than is morphine (compare p.o. and i.v. doses, ratio much smaller in levorphanol than in morphine), so that protection by an acetyl group is not necessary.
Given the existence of highly active (and legal?) derivates it seems like the morphinanes might be even the most interesting group of synthetic opiods, particularly concerning oral activity. The synthesis isn't too easy, but at least for the 3-OH derivatives it doesn't require elevated pressure. One step that looks pretty expensive and possibly dangerous is the reduction of cyclohexenyl acetonitrile. That exotic cobalt catalyst doesn't look very promising and LiAlH4 is the only alternative stated. I might add here that the Helv. Chim. Acta article states (p. 1439): "[..] by the reduction of nitrile XII with sodium and alcohol or with sodium and liquid ammonia cyclohexyl-ethylamine is always formed."

algebra
(Newbee)
10-12-03 14:27
No 464174
User Picture       cyclohexenyl ethylamine

Really nice info, shame that there is no easy alternative, (like Na/R-OH or a birch if these are easy...) to reduce the nitrile without also completely reducing the ring - why is there always some obstacle like LAH or 100 atm on some obscure hydrogenation catalyst that lurks in the interesting stuff...., arrrgh - frustration, frown .

Has anybee ever come across a specific lit-ref for the birch reduction of phenethylamine? Is ethylamine considered electron donating? - this is required of the ring substitution group to get the correct dihydro alignment in a birch. note also that a birch will give two unsaturated bonds and not one as in cyclohexenyl-ethylamine - the extra bond is reduced at a subsequent stage of the levorphanol synth. corrections welcome - working from slightly impaired memory here...

<edited>

Assholium
(Гуру)
10-12-03 16:50
No 464191
      cyclohexenyl ethylamine from PEA (Birch, NH3/Na)
(Rated as: excellent)

Ber., 92, p. 649, (1959)
20 g phenethylamin werden in 51 ccm absol Athanol gelost und zu 400-450 ccm flussigen Ammoniak gegeben, die sich in einem offenen Dewar-Gefab befinden. Unter Ruhren fust man inner halb weniger minuten 20 g. Natriumstuckchen hinzu, welche die Grosse von Reiskorhen haben. Nach beendeger Zugabe Lasst man wahrend mehrer Stunden das Ammoniak aus dem offenen Dewar-Gefab werdampfen, fugt troten waise 250-300 ccm H2O hinzu und ext. mit Ether -> 18 g, Sdp (12) = 80 C.

algebra
(Newbee)
10-13-03 10:24
No 464379
User Picture       Birch

Assholium, thank you smile . can any kind bee read german and provide a translation? What is the orientation of the dihydro ring? - is the birch reducing the pea to 2(2,5-cyclohexadienyl)) ethylamine or 2-(1,4 cyclohexadienyl) ethylamine\. Sorry Pimpo did not intend to lead off of the topic, frown ...

Rhodium
(Chief Bee)
10-13-03 12:26
No 464391
User Picture       Translation

I think the text could be translated as follows:

20g phenethylamine was dissolved in 51 mL anhydrous ethanol and added to 400-450 mL anhydrous liquid ammonia in an open Dewar container. With stirring, 20g rice-sized sodium pieces was added over a couple of minutes. After the addition was finished, the ammonia was allowed to evaporate over a few hours, whereafter 250-300 mL water was added and the product extracted with ether. Yield 18g, bp 80°C/12 mmHg.

Assholium
(Гуру)
10-13-03 19:15
No 464458
      Algebra, I check this article (Rudolf Grewe...

Algebra,

I check this article (Rudolf Grewe und Hans-Werner Otto, Die Synthese von Hexahydroisochinolinen) and really, they wrote about 2-(1,4-cyclohexadienyl)-ethylamine as product from liq. NH3/Na reduction.
Of course, this amine can be condensed with 4-MeO-phenylacetic acid to amide and then resulting amide can reduced to octahydroisoquinolune.
Usual reduction of PEA with Li in liquid ammonia or primary amine (common route described by Berkeser: JACS, 77, 3230, 6042 (1955)) gaves 2-(1-cyclohexeneyl)-ethylamine.

Pimpo
(Newbee)
10-21-03 13:52
No 465965
      erratum + three questions

First a little typo blush :

1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinoline

273 g (1 mol) p-methoxy-phenylacetic acid-(cyclohexenyl-ethyl)-amide is refluxed in 1000 ml benzene with 307 g POCl3 for 3 h. After cooling the reaction product [?] is poured on ice and the aqueous phase is made alkaline with ca. 30 % NaOH. The precipitated base is extracted with ether and the ethereal solution washed with water and dried. The crude 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinoline, which remains after distilling off the ether, is dissolved in the five-fold amount of methanol
and reduced at normal pressure in the presence of 50 g Raney-Nickel.

would of course be 3,4,5,6,7,8-hexahydro-isochinoline. This is then reduced to octahydro.

Now the first question. While idly reading here and there in the "Organikum", which is sure well-known to any bee interested in German chem literature, I noticed that it stated the reduction of 1 mol of nitrile to require 1/2 mol LiAlH4 and the reduction of a 1° amide to require 1 mol. The book actually encouraged the reader ("warum?") to think about these ratios and that is what I did. I came up with these equations (including hydrolysis):

R-CONH2 + LiAlH4 + 3 H2O --> RCH2NH2 + LiOH + Al(OH)3 (1 mol required, 2 mol used!)

R-CN + 1/2 LiAlH4 + 2 H2O --> RCH2NH2 + 1/2 LiOH + 1/2 Al(OH)3 (1/2 mol required, 1 mol used!)

So why does the synth use twice the required amount for both the amide and the nitrile? I know that a slight excess of LiAlH4 is commonly used, but so much? I mean, there are no other functional groups that could react with the LiAlH4. Might this be a mistake, or did they want to fool their competitors?

Second question. Could 1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydro-isochinoline be reduced to octahydro with LiAlH4? It is an imine and I see no groups interfering.

Third question. This is only directed to those who have read the synthesis thoroughly. Could p-methoxy-phenylacetic acid-(cyclohexenyl-ethyl)-amide be condensed to 1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydro-isochinoline with P2O5 instead of POCl3 just like the plain phenylacetic acid-(cyclohexenyl-ethyl)-amide to 1-benzyl-3,4,5,6,7,8-hexahydro-isochinoline? Might SOCl2 possibly be used instead of POCl3?

Answers to these questions would really bee helpful!

Thanks, Pimpo

P.S. algebra, I think we shouldn't give up on this one. Looks so damn tasty tongue ! I just read about Urushibara catalysts, might they be applied here? The U-Co looks suitable for the nitrile! Really have to learn more about those buggers.

slappy
(Hive Addict)
10-22-03 09:16
No 466093
      2-Cyclohexylethylamine can also be made from...

2-Cyclohexylethylamine can also be made from phenethylamine (PEA) by hydrogenating with PtO2 or Pt black in AcOH at 20atm H2.

Assholium
(Гуру)
10-22-03 10:58
No 466101
      2-cyclohexylethylamine

2-Cyclohexylethylamine can also be made from phenethylamine (PEA) by hydrogenating with PtO2 or Pt black in AcOH at 20atm H2

2-Cyclohexylethylamine is almost useless here, for this rxn (Bishler-Niepiralski cyclization with formation 3,4,5,6,7,8-hexahydroisoquinoline) we need one or two double bonds in cyclohexane ring.

Assholium
(Гуру)
10-22-03 11:03
No 466102
      yet another example: 3-phenoxy-N-methylmorphinan
(Rated as: excellent)

Patent US4194044: Process for preparing 3-phenoxy-morphinans

EXAMPLE 6
N-[2-(1-Cyclohexen-1-yl)-ethyl)-4-phenoxyphenyl acetamide
A mixture of 1.26 g (0.01 mol) of cyclohexen-(1)-yl-ethylamine and 1.9 g of 4-phenoxyphenylacetic acid in 20 ml of xylene was heated at reflux for 16 hrs with removal of the water by means of a Dean-Stark apparatus. After evaporation of the solvent, the crude product was crystallized from cyclohexane-hexane mixture to give 2.6 g (76%) of pure N-[2-(l-cyclohexen-l-yl)-ethyl]-4-phenoxyphenyl acetamide, mp 74°-75".

EXAMPLE 7
(±)-1-(p-Phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline
A mixture of 2.5 g (0.01 mol) N-[2-(l-cyclohexen-l-yl)ethyl]-4-phenoxyphenyl acetamide, 5.0 ml of POCl3 and 20 ml of toluene was heated at reflux under nitrogen for 2 hrs. After evaporation of the solvent and excess reagent there was obtained (±)-1-(p-phenoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline as residue. The residue was triturated with pet ether (2 * 10 ml). The pet ether insoluble hexahydro compound was dissolved in methanol and immediately reduced by portionwise addition of 1.0 g of sodium borohydride. The reaction mixture was stirred at room temperature for 4 hrs. The methanol was distilled off and the residue was partitioned between ether (60 ml) and dilute aqueous ammonium hydroxide. The ether solution was washed with water, dried and evaporated to give 1.6 g (69%) of crude (±)-l-(p-phenoxybenzyl)-l,2,3,4,5,6,7,8-octahydroisoquinoline.
For purification, 1.5 g (0.005 mole) of the above crude (±)-l-(p-phenoxybenzyl)-l,2,3,4,5,6,7,8-octahy-droisoquinoline in 5 ml of acetone was treated with 0.42 g of oxalic acid and allowed to crystallize. The crude oxalate was recrystallized from ethanol (30 ml) to give 1.61 g (84%) of pure (±)-1-(p-phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline oxalate, mp 176°-178°.

EXAMPLE 5
(±)-1-(p-Phenoxybenzyl)-2-formyl-l,2,3,4,5,6,7,8-octahydroisoquinoline
To a solution of 0.78 g (0.002 mol) of (±)-1-(p-phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline in 5 ml of chloroform was added 0.42 g of chloral in 1 ml of chloroform dropwise. After the mixture had been stirred at room temperature for 3 hrs it was diluted with IS ml of chloroform and washed with 4 N hydrochloric acid (10 ml) and water (10 ml). After drying, the solvent was removed under reduced pressure to give 0.81 g (96%) of crude (±)-1-(p-phenoxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For characterization, a sample of this compound was distilled, bp 225°-227° (0.08 mm Hq).

EXAMPLE 8
(±)-3-Phenoxy-N-formylmorphinan
(±)-1-(p-Phenoxybenzyl)-2-formyl-l,2,3,4,5,6,7,8-octahydroisoquinoline, 24.5 g (0.07 mol), was combined under stirring with 120 g of phosphoric acid which had been mixed with 1.0 g of concentrated sulfuric acid and the mixture was heated in a nitrogen atmosphere to 70°. The resulting homogeneous solution was kept at 70° for 48 hrs. The mixture was cooled in an ice bath and ice-water was added. The resulting suspension was extracted with ethyl acetate (100 ml). The ethyl acetate solution was washed with water and dried. Removal of the solvent gave 23.3 g (95%) of crude (±)-3-phenoxy-N-formylmorphinan.
For characterization a sample of the morphinan was isolated from the above mixture by preparative tlc on silica gel (eluted with ethyl acetate) and distilled, bp 210°-220°(0.1 mm Hg).

EXAMPLE 9
(± )-3-Phenoxy-N-methylmorphinan
To a suspension of 1.1 g of lithium aluminum hydride in 120 ml of anhydrous tetrahydrofuran, 10.8 g (0.03 mol) of crude (±)-3-phenyl-N-formylmorphinan in 50 ml of tetrahydrofuran was added dropwise. After the mixture had been refluxed for 3 hrs, it was cooled to room temperature and ethyl acetate followed by water were added dropwise. The resulting suspension was dried, filtered and the filtrate concentrated in vacuo to give a dark brown oil which was distilled, bp 170°-180° (0.05 mm Hg) to afford 7.6 g (73%) of crude (±)-3-phenoxy-N-methylmorphinan.
This crude morphinan, 7.6 g (0.02 mole) on treatment with oxalic add (2.4 g) in ether (40 ml) afforded 6.8 g of crude oxalate mp 110°-120°. Several recrystallizations from acetonitrile gave 3.6 g (37%) of pure (±)-3-phenoxy-N-methylmorphinan oxalate, mp 144°-146°.

Megatherium
(Hive Bee)
10-26-03 01:27
No 466777
      R. Grewe

All these refs. are by Grewe, which is kind of a pioneer in the morphinan synthesis :
Chem. Ber. (1948) vol 48 p 289
Ann. (1949) vol 564 p 161
Angew. Chem. (1947) vol 59 p 194

And, J. Chem. Rev. (1977) p 77 contains a detailed discussion of the Grewe cyclization.

Rhodium
(Chief Bee)
10-26-03 02:51
No 466790
User Picture       Review: Benzomorphan Synth./React./Character.
(Rated as: good read)

Your last ref was a bit off, but I found the review anyway:

Benzomorphans: synthesis, stereochemistry reactions, and spectroscopic characterizations
David C. Palmer and Michael J. Strauss
Chem. Rev. 77, 1-42 (1977) (https://www.rhodium.ws/pdf/benzomorphan.review.pdf)

Abstract
The problems of prolonged physical pain and mental anguish, the efficacy of opiates in ameliorating these experiences, and the consequent difficulties of physical dependence and addiction associated with opiate use have been the subject of extensive study by chemists, biochemists, pharmacologists, and physicians for many decades. The problems of opiate addiction in the United States and the associated social trauma have served, in part, to intensify efforts directed toward understanding the basic mechanisms of the action of these drugs and to intensify the search for a better analgesic which has no harmful side effects and does not induce physical dependence. The detailed mechanisms of action are still in large part unknown and the ideal analgesic has not yet been found, but substantial progress is being made.

Pimpo
(Newbee)
11-24-03 16:46
No 472878
      Resolution of Racemorphan with D-Tartaric Acid

First, a late thank you to Assholium, that patent is instructive wink !

Interest in this subject seems to have declined recently, but I am still following this up, I found the following in Helv. Chim. Acta 34 (1951), p. 2211-2217, '271. Oxy-morphinane' by O. Schnider and A. Grüssner:

The article also mentions the preparation of (-)-3-hydroxy-N-allyl-morphinan - this is Levallorphan, isn't it? -, which cannot easily be prepared from the racemate. I will omit this.

The resolution of racemorphan is described on p. 2213, here my translation:

(-) and (+) 3-Hydroxy-N-methyl-morphinane

22.8 g Racemic 3-hydroxy-N-methyl-morphinane is dissolved with 13.2 g D-tartaric acid in 300 ml water and the filtrated solution is allowed to stand at RT for 24 h after adding seed crystals of the levorotary D-tartaric salt [i.e. the corresponding salt of the title compound!?]. The crystals are filtered off with suction and washed twice with 5 ml water and then dried. Yield 12.1 g.

To the mother liquor is added dextrorotary D-tartaric salt and it is stirred for 4 - 5 h, the crystalline mass is filtered off with suction and washed twice with 5 ml water and then dried. Yield 10.2 g.

By concentrating, adding seed crystals and letting stand practically quantitative yields of the (-) and (+) tartrate are obtained.

The article has photos (microscope) of the (-) and (+) tartrates:

(-) looks like rectangular plates
(+) looks like very fine needles that are tied together in the middle in bunches. Kind of like a bursting star or so.

P.S.: Erratum: The article reported earlier by me was found in Helv. Chim. Acta 33 (1950) not in 23 (1950), which of course doesn't exist.

Pimpo
(Hive Bee)
12-03-03 23:38
No 474563
      N-Arylalkyl-morphinanes
(Rated as: good read)

Recently I found some more interesting stuff about my favourite field of research in the library:

Helvetica Chimica Acta, 40 (1957), p. 1232-1441, and J. Hellerbach and O. Schnider - '138. Hydroxy-morphinane (11. Mitteilung)'

It contains experimental procedures for N-arylalkyl-morphinanes, as well as some physical data and confirms the high activity of the N-phenethyl compounds (up to 50 - 70 x morphine). N-phenylpropyl compounds are stated to have weak effects, the phenylbutyl compounds being somewhat more active. All this confirms the activity data posted recently. I will translate the more interesting parts now, starting from p. 1235 - all elemental analysis data is omitted:

Experimental Part

For each method only one method is described in detail.

Method A (-)-3-Hydroxy-N-phenylethyl-morphinane. 70 g (+)-1-p-Hydroxybenzyl-1,2,3,4,5,6,7,8-octahydro-isochinoline are dissolved in 350 ml DMF and after addition of 40 g anhydrous K2CO3, 53.2 g beta-phenylethyl-bromide are added dropwise with stirring. The reaction product is stirred overnight in an oil bath having a temperature of 100 °C, mostly freed of DMF at waterpump-pressure and dissolved in ether. The ethereal solution is washed with water, dried with anhydrous Na2SO4 and the ether is distilled off. The remaining base (ca. 100 g), dissolved in acetone, immidiatelly yields (-)-1-p-Hydroxybenzyl-2-phenylethyl-1,2,3,4,5,6,7,8-octahydro-isochinoline oxalate upon addition of oxalic acid, and melts at 158 - 159 °C from i-PrOH. [alpha]22D = - 55 ° (c = 1 in MeOH).
Hydrobromide: mp 203 - 205 °C (from EtOH-ether), [alpha]21D = - 47.3 ° (c = 1 in MeOH)

100 g (-)-1-p-Hydroxybenzyl-2-phenylethyl-1,2,3,4,5,6,7,8-octahydro-isochinoline oxalate are heated with stirring with 500 g 99 % crystalline H3PO4 at 140 °C (reaction temperature) for 72 h, carefully diluted with 1200 ml water afterwards and then boiled for another hour. The reaction mixture is cooled, 600 ml n-BuOH are added on top ['überschichten'] and conc. NH3 is added dropwise with stirring until the mixture is slightly alkaline to phenolphtaleine at such a rate that the neutralization temperature is 50 - 60 °C. After cooling ca. 400 ml benzene are added, the aqueous phase is removed from the benzene-butanol layer and the latter is washed neutral with water. Upon distilling off the benzene-butanol mixture in vacuo the base crystallizes. Recrystallized from DMF the (-)-3-Hydroxy-N-phenylethyl-morphinane melts at 243 - 245 °C.
Hydrobromide: mp. 300-301 °C (from water-EtOH), [alpha]20D = - 63.12 °, (c = 3,27 in MeOH).
[? can't read if D or L]-tartrate. 1 H2O: mp. 125 - 126 °C (from i-PrOH), [alpha]20D = - 42.75 ° (c = 0.983 in water).
Phosphate: mp. 190 - 192 °C (from water)
Camphorsulfonate: mp. 218 - 220 °C (from water)
Methyl-'onium-bromide: mp. 239 - 240 °C (from EtOH), [alpha]20D = - 42.81 ° (c = 1.155 in MeOH)

This is it for now, more will bee presented some other day. I think the use of p-hydroxybenzyl-1,2,3,4,5,6,7,8-octahydro-isochinoline instead of the methoxy-derivative as starting material has mainly to do with chirality, the latter should work too, shouldn't it? That would make phenomorphan just as accessible as dromoran crazy .

P.S.: I just noticed that I have been promoted to hive bee from new bee, that's very nice smile !

Pimpo
(Newbee)
12-06-03 11:05
No 474986
      More on N-Arylalkyl-morphinanes
(Rated as: good read)

There follows on pages 1236 - 1239 a table of physical data of various derivatives. Onfortunately most of the mp.s are unreadable in my copy. On inquiry I could (might take a while) look that data up in the library. The only thing to report at this point is that 3-hydroxy-N-phenethylmorphinane has mp 300 - 301 °C from EtOH-water too, so this might be an alternative for recrystallizing the product.

So here comes p. 1240 - 1241:

Method B (-)-3-Hydroxy-N-(p-nitro-beta-phenylethyl)-morphinane. 8.2[the last figure I can't read, I think it's 8.25 or 8.26, gonna check that] (-)-3-hydroxy-morphinane are heated with 7.8 g p-nitro-beta-phenylethyl-bromide and 5 g anhydrous K2CO3 in 100 ml DMF with stirring for 6 h in an oilbath heated to 100 °C. The reaction product is poured in water and extracted with ether. After washing and drying the ethereal solution and evaporating the solvent the residue is converted with ethanolic HCl to the hydrochloride, which on rubbing['anreiben'] with acetone crystallizes immidiatelly and melts at 247 °C from EtOH. [alpha]13D = - 84.6 ° (c = 1 in MeOH)

(-)-3-hydroxy-N-(p-amino-beta-phenylethyl)-morphinane. When reducing 36.5 (-)-3-hydroxy-N-(p-nitro-beta-phenylethyl)-morphinane in 300 ml MeOH in the presence of 20 g 5 % Pd on charcoal the calculated amount of hydrogen is absorbed rapidly. (-)-3-hydroxy-N-(p-amino-beta-phenylethyl)-morphinane crystallizes already while evaporating the methanolic solution. From acetone it melts at 196 - 199 °C, [alpha]20D = - 107.6 °

Method C 3-Hydroxy-N-(3',4'-methylenedioxy-phenylethyl)-morphinane. 12.15 g (-)-3-hydroxy-morphinane are dissolved in 160 ml DMF with stirring at 100 °C, 7.3 g powdered anhydrous K2CO3 is added and 10.3 g 3,4-methylenedioxy-phenylacetyl-chloride is added dropwise. After 2 h heating at 120 °C (temperature of bath) the mixture is filtrated while hot, and the solution is evaporated at waterpump-pressure. The residue is disolved in butanol-benzene (1 : 1) and the solution is sequentially washed with dil. HCl, water, NaHCO3-solution and finally until neutral with water. The benzene-butanol solution is evaporated in vacuo. The residue is disolved in 80 ml absolute THF and at 50 °C slowly added to a stirred suspension of 5.7 g LAH in 250 ml THF. After 3 h water is added while cooling with ice until the excess LAH is destroyed. The THF solution is decanted, the residue extracted with ether, the THF- and ether solution is dried with K2CO3, filtrated and evaporated. The residue which melts at 176 - 178 °C from MeOH, is disolved in 80 ml MeOH and made slightly acidic against congo red with methanolic HCl. 18 g of the hydrochloride crystallize, mp. 290 - 292 °C. [alpha]10D = - 75.53 ° (c = 1.0428 in MeOH).

Method D is omitted, it describes the preparation of (-)-3-hydroxy-N-(gamma-phenylpropargyl)-morphinane from (-)-3-hydroxy-morphinane, HCHO and PhCCH and it's reduction to the phenallyl compound.

Method E. (-)-3-Hydroxy-N-phenacyl-morphinane. To the solution of 12.15 g (-)-3-hydroxy-morphinane im 150 ml DMF is added while stirring 7.3 g finely powdered K2CO3 and 11 g bromo-acetophenone. CO2 and heat are evolved. After stirring for 1/2 h the mixture is evaporated and the residue recrystallized from EtOH. Yield 14 g (78 %), mp. 173 - 175 °C.
Hydrochloride: mp. 278 - 279 °C (from EtOH - ether), [alpha]20D = - 71.91 ° (c = 1.022 in MeOH)

(-)-3-Hydroxy-N-(2'-hydroxy-2'-phenylethyl)-morphinane. 2 g (-)-3-Hydroxy-N-phenacyl-morphinane is disolved in 100 ml MeOH and reduced in the presence of 5 g 5 % Pd on charcoal. After filtrating and evaporating the MeOH in vacuo the hydrochloride is obtained from EtOH - ether [?]. mp. 244 - 245 °C, [alpha]20D = - 70.6 ° (c = 1.024 in MeOH).

[summary omitted]

So that's it, hope it will help somebee some day crazy .

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